Summary There is substantial variation in recovery after pediatric traumatic brain injury (TBI). If we could understand the underpinnings behind this variation, then treatments could be optimized to reduce the profound negative societal and economic impact associated with pediatric TBI. Predictors of recovery following TBI, particularly the roles of genes and environment, are incompletely understood. Elucidation of genetic and environmental influences on recovery after pediatric TBI is critically needed to advance development of precision medicine strategies. Novel systems biology analyses conducted by our group indicate genetic factors within two main biologic processes, response to injury (cell proliferation, cell death, inflammatory response, cellular metabolism) and neurocognitive and behavioral reserve (neurodevelopment, cognition, and behavior), are likely associated with recovery after TBI. An approach that seeks to identify genes and variants over- represented (gene-enrichment) across these biologic processes would improve upon prior candidate gene approaches. Genetic variants implicated in recovery after TBI interact with home and family environmental factors to influence cognitive and behavioral outcomes in other pediatric populations; however, the effects of the interaction between genes and environment on recovery after pediatric TBI have not been explored. The objective of this proposal is to understand the interplay between genetically influenced biologic processes and environment with respect to recovery after pediatric TBI. We hypothesize that genetic variants overrepresented in biologic processes important to TBI recovery will be associated with global, neurocognitive, and neurobehavioral functioning and that environmental factors will interact with genetic factors to influence recovery after severe pediatric TBI. We will collect salivary DNA samples from approximately 338 children participating in the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT, U01 NS081041). The primary outcome will be global functioning assessed by the pediatric Glasgow Outcome Scale-Extended (GOSE) at 3, 6, and 12 months post injury and secondary outcomes will include a comprehensive assessment of cognitive and behavioral functioning at 12 months post injury. We will use an analytic approach that seeks to identify genes and variants associated with recovery that are over-represented (gene-enrichment) across response to injury and neurocognitive and behavioral reserve biologic processes. Mixed model analyses will be used to evaluate the association of genotypes with recovery after severe pediatric TBI and to elucidate the association of environmental factors (family functioning, parenting practices, home environment, and socioeconomic status) with recovery. How genetic and environmental factors and genetic and early clinical factors interact to influence recovery after severe pediatric TBI will also be evaluated. This project will provide critically needed information to inform individualization of prognosis and development of novel, precision medicine approaches for pediatric TBI, which are considerably lacking for this population.